Z-selective Olefination Research Articles

A New Organocatalytic Desymmetrization Reaction Enables the Enantioselective Total Synthesis of Madangamine E.

The enantioselective total synthesis of madangamine E has been completed in 30 steps, enabled by a new catalytic and highly enantioselective desymmetrizing intramolecular Michael addition reaction of a prochiral ketone to a tethered β,β′-disubstituted nitroolefin. This key carbon–carbon bond forming reaction efficiently constructed a chiral bicyclic core in near-perfect enantio- and diastereo-selectivity, concurrently established three stereogenic centers, including a quaternary carbon, and proved highly scalable. Furthermore, the pathway and origins of enantioselectivity in this catalytic cyclization were probed using density functional theory (DFT) calculations, which revealed the crucial substrate/catalyst interactions in the enantio-determining step. Following construction of the bicyclic core, the total synthesis of madangamine E could be completed, with key steps including a mild one-pot oxidative lactamization of an amino alcohol, a two-step Z-selective olefination of a sterically hindered ketone, and ring-closing metatheses to install the two macrocyclic rings.

Total Synthesis of Meayamycin B.

Meayamycin B is currently the most potent modulator of the splicing factor 3b subunit 1 and used by dozens of research groups. However, current supply for this natural product analogue is limited because of the lengthy synthetic scheme. Here, we report a more concise, more cost-effective, and greener synthesis of this compound by developing and employing a novel asymmetric reduction of a prochiral enone to afford an allylic alcohol with high enantioselectivity. In addition to this reaction, this synthesis highlights a scalable Mukaiyama aldol reaction, Nicolaou-type epoxide opening reaction, stereoselective Corey-Chaykovsky-type reaction, and a modified Horner-Wadsworth-Emmons Z-selective olefination. We also discuss a Z-E isomerization during the α,β-unsaturated amide formation. The new synthesis of meayamycin B consists of 11 steps in the longest linear sequence and 24 total steps.

Total syntheses of shizukaols A and E

Shizukaols possess a common heptacyclic framework containing more than ten contiguous stereocenters and potential biological activities. Here we report that the total syntheses of shizukaols A (1) and E (2), two lindenane-type dimers from the Chloranthaceae family, are achieved via a modified biomimetic Diels–Alder reaction. The common crucial biomimetic diene 23 and ethylene species (6, 17) are obtained through either a highly Z-selective olefination of α-siloxy ketone with ynolate anions or an intramolecular Horner–Wadsworth–Emmons olefination from commercially available Wieland–Miescher ketone (7). This synthetic approach here opens up practical avenues for the total syntheses of the intriguing Chloranthaceae family members, as well as the understanding of their relevant biological action in nature.

Application of Horner–Wadsworth–Emmons olefination for the synthesis of granulatamide A, its E isomer and other amides of tryptamine

Horner–Wadsworth–Emmons (HWE) Z-selective olefination was used for the first synthesis of a naturally occurring cytotoxic tryptamine derivative, granulatamide A. The E-isomer of granulatamide A and two other tryptamine derived amides were synthesized by E-selective HWE olefination.

The effects of C–S and C–Se bonds on torquoselectivity: stereoselective olefination of α-thio and α-selenoketones with ynolates

Highly Z-selective olefination of acyclic α-thio and α-selenoketones with ynolates has been achieved, and the theoretical calculations of the transition states in the ring-opening of the intermediates, the β-lactone enolates, revealed that the torquoselectivity was controlled by the secondary orbital interactions between the σ orbital of the C–S bond or a lone pair orbital on the S and σ ∗ orbitals of the breaking C–O bond, and the σ orbital of the breaking C–O bond or a lone pair orbital on the O on the ring and the σ ∗ orbitals of the C–S bond. The synthetic applications of the resulting olefins are also shown.

Synthetic studies aimed at the elucidation of the stereostructure of the aggregation pheromone, 2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol, produced by the male stink bug Erysarcoris lewisi

The male-produced aggregation pheromone of the stink bug Erysarcoris lewisi Distant was shown to be one of the two diastereomers of (2 Z,6 R)-2-methyl-6-(4′-methylenebicyclo[3.1.0]hexyl)hept-2-en-1-ol by synthesizing and bioassaying (2 E,6 R)-, (2 E,6 S)-, (2 Z,6 R)-, and (2 Z,6 S)-isomers. These were synthesized from the enantiomers of citronellal by employing an intramolecular α-ketocarbene addition to a double bond and the E-selective or Z-selective olefination of a formyl group as the key steps. A reliable method was developed for the preparation of ethyl 2-(di- o-tolylphosphono)propanoate, Ando’s reagent for Z-selective olefination.

Hyperconjugative effect of C–Ge bonds: synthesis of multisubstituted alkenylgermanes via torquoselective olefination of acylgermanes with ynolates

The first highly Z-selective olefination of acylgermanes with ynolates affording multisubstituted alkenylgermanes was achieved. The torquoselectivity was ascribed to the hyperconjugative effect of C–Ge bonds in the transition state. The resulting ( Z)-β-trialkylgermylacrylic acid has a hypervalent structure, which was converted into novel germalactones. A stereochemical complementary olefination via protonation of the β-lactone enolate, followed by decarboxylation, was also achieved.

Method for the Rapid Synthesis of Highly Functionalized 2-Hydroxy-1-naphthoates. Syntheses of the Naphthoic Acid Components of Neocarzinostatin Chromophore and N1999A2.

We describe a four-step sequence for the synthesis of complex 2-hydroxy-1-naphthoic acids involving Z-selective olefination of benzaldehyde derivatives with a novel dioxolenone-containing phenyl phosphonate reagent, followed by dioxolenone cleavage with alkaline trifluoroethanol and oxidative cyclization (Mn(OAc)3) of the resultant trifluoroethyl β-keto esters.

Method for the Rapid Synthesis of Highly Functionalized 2-Hydroxy-1-naphthoates. Syntheses of the Naphthoic Acid Components of Neocarzinostatin Chromophore and N1999A2

We describe a four-step sequence for the synthesis of complex 2-hydroxy-1-naphthoic acids involving Z-selective olefination of benzaldehyde derivatives with a novel dioxolenone-containing phenyl phosphonate reagent, followed by dioxolenone cleavage with alkaline trifluoroethanol and oxidative cyclization (Mn(OAc)(3)) of the resultant trifluoroethyl beta-keto esters. [reaction: see text]

Synthetic studies of microtubule stabilizing agent peloruside A: an asymmetric synthesis of C10-C24 segment.

An asymmetric synthesis of the C10-C24 fragment of the potent antitumor macrolide, peloruside A is described. All three stereogenic centers have been enantioselectively constructed utilizing Evans alkylation, Brown asymmetric allylboration, and a substrate controlled epoxide formation. Other key reactions involved Grubbs's ring-closing olefin metathesis and Ando's Z-selective olefination reaction.

A practical total synthesis of plaunotol via highly Z-selective Wittig olefination of α-acetal ketones

Plaunotol (1), a known antiulcer drug, is the most important component of the Thai folk medicinal plant, Plau-noi, which has remarkable antipeptic ulcer activity. Recently, it was found that plaunotol (1) has antibacterial activity against Helicobacter pylori, a causative agent in gastric ulcers and gastric adenocarcinoma, for example. In our investigation of the practical synthesis of 1, we have developed an efficient method for stereoselective synthesis of trisubstituted olefins via a Z-selective Wittig reaction. The olefination of readily available aliphatic α-acetal ketones with triphenylphosphonium salts in the presence of a potassium base and 18-crown-6 ether proceeded with excellent Z-selectivity. The Z-selective olefination provides a useful method for the construction of a range of trisubstituted olefin moieties; the practical and stereoselective total synthesis of plaunotol (1) was achieved via this Wittig reaction.

Z-Selective olefination of base-sensitive chiral β-hydroxy-α-aminoaldehydes using a modified Horner-Wadsworth-Emmons reaction

The HWE Reaction of base-sensitive chiral β-hydroxy-α-aminoaldehydes (serinals) was achieved under mild conditions with complete Z-selectivity using bis(trifluoroethyl) phosphonates and LiCl, DBU in THF. The use of the corresponding dimethyl phosphonates resulted in a mixture of E- and Z-configurated products, the ratio of which was found to depend on the size of the ester group.